The present invention relates to a composition for prophylaxis and/or treatment of keratoconjunctivitis sicca (dry eye syndrome) comprising vitamin D.
Keratoconjunctivitis sicca is called xe2x80x9cdry eyexe2x80x9d and is the focus of the discussion by ophthalmologists and others. xe2x80x9cOphthalmology New Insight 5xe2x80x9d published by Medical Review Co., Ltd. describes corneal epithelial cells, vitamin A deficiency and keratoconjunctivitis sicca and refers to vitamin D in relation to epidermis. xe2x80x9cDry eyexe2x80x9d, a medical journal published by Nihon Hyoronsha presents widely keratoconjunctivitis sicca. According to them, they say that vitamin A deficiency is deeply involved in the disease of corneal conjunctival epithelium but vitamin D deficiency is not involved because there is not clinically present the disorder of corneal conjunctival epithelium in vitamin D deficiency.
The journal xe2x80x9cDry eyexe2x80x9d classifies the dry eye syndrome into syndrome of decrease in the secretion of the lacrimal fluid and the disorder of keratoconjunctivitis sicca, and describes that they are due to decrease in the secretion of the lacrimal fluid and the disorder of cornea and conjunctiva. It is considered that keratoconjunctivitis sicca is caused by asthenopia which is caused by the reduction of the number of twinkling due to long time watching of video display terminals or televisions, or by dust in the windy day, ozone, nitrogen oxides, and the like. They say, for some reasons, cornification is caused in corneal epithelial cells or conjunctival Golbet cells; as a result, the lacrimal fluid cannot be kept in cornea or conjunctiva, or inflammatory reaction on cornea or conjunctiva extraordinarily reduces the mucin layer, the aqueous layer or the oil layer which constitutes the lacrimal fluid to cause keratoconjunctivitis sicca.
There have been proposed as therapy of keratoconjunctivitis sicca, the use of artificial lacrimal fluid, goggles for dry eye, herb medicine, dacryon plug and the like.
In general, the term xe2x80x9cvitamin Dxe2x80x9d means vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) exhibiting a high anti-rachitis activity. It has been known that the vitamin D undergoes a change in its molecular structure (hydroxylation) in the liver and kidney and that it is thus converted into active vitamin D having high biological activities. It has also been supposed that vitamin D itself has, to some extent, certain biological activities.
Vitamin D""s for therapy are administered to patients per oral route or by injection. It has been recognized that vitamin D""s have not only a calcium-regulatory effect, but also other biological activities since the discovery of the active vitamin D3, i.e., calcitriol (1xcex1,25-dihydroxy cholecalciferol) as a derivative of cholecalciferol. Active vitamin D""s include those carrying a hydroxyl group on one or both of the C1 position on the sterol A ring and the C25 position on the side chain, for example, calcitriol (1xcex1,25-dihydroxy vitamin D), 1xcex1,24-dihydroxy vitamin D, xcex1-calcidol (1xcex1-monohydroxy vitamin D), calcifedol (25-monohydroxy vitamin D), 1xcex1,24,25-trihydroxy vitamin D, 1xcex2,25-dihydroxy vitamin D, 22-oxacalcitriol, and calcipotriol. Analogues thereof include dihydrotachysterol. The presence of active vitamin D receptors in cells has been discovered and there have been conducted studies on modification of cellular activities because of the ability of the active vitamin D""s to control the production of various cytokines.
An object of the present invention is to provide an ophthalmic composition for prophylaxis and/or treatment of cornification of corneal or conjunctival cells which is caused by the reduction of the number of twinkling due to long time watching of the screen of televisions, or by dust in the windy day, ozone, nitrogen oxides, and the like, that is, to provide an ophthalmic composition for prophylaxis and/or treatment of keratoconjunctivitis sicca which is a syndrome of decrease in the secretion of the lacrimal fluid and disorders of conjunctiva and cornea.
The present invention is an ophthalmic composition for prophylaxis and/or treatment of keratoconjunctivitis sicca, which comprises, as an effective component, at least one member selected from the group consisting of vitamin D, active vitamin D, and active vitamin D analogues.
Particularly preferred vitamin D""s used in the present invention include ergocalciferols and cholecalciferols, active vitamin D""s include those carrying a hydroxyl group on one or both of the C1 position on the sterol A ring and the C25 position on the side chain, and vitamin D analogues include dihydrotachysterol.
The composition of the present invention does not use anti-rachitic activities of vitamin D but proceeds for conjunctival Golbet cells or corneal epithelial cells which have cornified or will cornify to perform normal differentiation. Namely, the composition administered is considered to accelerate differentiation of conjunctival Golbet cells or corneal epithelial cells to normalize the cells when the keratoconjunctivitis occurs. The activity of vitamin D administered to perform cellular differentiation is believed to be far lower than that of active form of vitamin D having biological activity.
The composition of the present invention comprises at least one member selected from the group consisting of vitamin D, active vitamin D and active vitamin D analogues which are oil-soluble and formulated into eye drops for local use. The composition prevents and/or cures the cornification of conjunctival or corneal epithelial cells. Specific examples of the effective component of the composition of the present invention include ergocalciferols, cholecalciferols, calcitriol (1xcex1, 25-dihydroxy vitamin D), 1xcex1,24-dihydroxy vitamin D, a -calcidol (1xcex1-monohydroxy vitamin D), calcifedol (25-monohydroxy vitamin D), 1xcex1,24, 25-trihydroxy vitamin D, 1xcex2, 25-dihydroxy vitamin D, 22-oxacalcitriol, calcipotriol and dihydrotachysterol.
The composition of the present invention can be formulated in various forms but most preferably in the form of eye drops. The concentration of the effective component in the composition of the present invention is suitably in the range of 0.001 to 100 xcexcg/ml since the composition is locally administered. The effective component of the present invention, i.e., vitamin D, active vitamin D and active vitamin D analogues are not cytotoxic. Accordingly, the composition would not adversely affect conjunctival or corneal epithelial cells as long as the formulation is physiological.
When vitamin D or active vitamin D formulation is orally administered in a large amount, hypervitaminosis D is observed wherein blood calcium and phosphate increase to cause calcification in soft tissues such as kidney, artery, smooth muscle, and lung. The effective component of the present invention, i.e., vitamin D, active vitamin D and active vitamin D analogues is effective for prophylaxis and/or treatment of keratoconjunctivitis sicca even if it is administered in a small amount.
Accordingly, if it distributes to some extent into blood through eye mucosa, the side effects mentioned above would not be developed. Vitamin D, active vitamin D and active vitamin D analogues used in the present invention may be natural or artificial one. Examples of artificial active vitamin D analogues include xcex1-calcidol (1xcex1-monohydroxy vitamin D), 22-oxacalcitriol (OCT), calcipotriol (MC 903) and dihydrotachysterol.
The lacrimal fluid is amphiphilic and viscous. If the composition of the present invention is used in the form of eye drops, viscous media such as polysorbate, polyvinyl alcohol, methyl cellulose, sodium hyaluronate, chondroitin sulfuric acid, plant oils, and fats and oils are preferably used to prepare a viscous formulation so that the vitamin D""s in the formulation can be retained on the surface of the eye balls for a long time to show a higher and longer effect for prophylaxis and/or treatment of keratoconjunctivitis sicca. Viscosity of the eye drops is preferably in the range of 0.01 to 10 poise.